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Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels

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Science  10 Jul 2015:
Vol. 349, Issue 6244, pp. 187-191
DOI: 10.1126/science.aab1091

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Structure of a sterol sensor

The aberrant accumulation of sterols contributes to heart attack and stroke. Two proteins embedded in the membrane of the endoplasmic reticulum, Insig-1 and Insig-2, are key players in the cellular pathway that regulates cellular sterol levels. Ren et al. report the structure of a mycobacterial homolog of Insig. The structure, together with biochemical experiments, suggests how Insig interacts with other components of the sterol regulatory pathway.

Science, this issue p. 187

Abstract

Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane–embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element–binding protein pathway.

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